Antiatherosclerotic tetrasubstituted ureas and thioureas

ABSTRACT

Tetrasubstituted urea and thiourea compounds useful as antiatherosclerotic agents, compositions thereof and processes for their preparation.

BACKGROUND OF THE INVENTION

This invention relates to new tetrasubstituted urea and thioureacompounds useful as pharmaceutical agents. The novel compounds of thepresent invention are antiatherosclerotic agents capable of amelioratingatherosclerosis by counteracting the formation or development ofatheromatous lesions in the arterial wall of mammals. The invention alsorelates to the chemical synthesis of the novel compounds disclosedherein. In addition, the invention pertains to novel pharmaceuticalcompositions for the utilization of these compounds in the treatment ofdisease in mammals. Further, the invention contemplates methods fortreating atherosclerosis in a manner designed to prevent, arrest, orreverse the course of the disease.

A variety of urea and thiourea compounds can be found in the literature,for example, in J. Med. Chem. 18, 1024 (1975); Chem. Absts. 95: 6758m(1981) and 91: 74631 g (1979); U.S. Pat. Nos. 2,688,039; 3,335,142;3,856,952; 3,903,130; and in West German Offenlegungsschrift No. 29 28485. The compounds found in the literature are disclosed as being usefulherbicides, plant growth regulators, bactericides, pesticides,fungicides, algacides, photographic sensitizers, antihelmintics,sympatholytics and antivirals. Those urea compounds found inOffenlegungsschrift No. 29 28 485 are disclosed as useful in inhibitinglipid absorption. There are, however, no literature referencesdisclosing the tetrasubstituted urea and thiourea compounds of thepresent invention or their use in the treatment of atherosclerosis orhyperlipidemia.

Atherosclerosis is a form of arteriosclerosis characterized by lipidaccumulation in and thickening of the arterial walls of both medium andlarge-sized arteries. Arterial walls are thereby weakened and theelasticity and effective internal size of the artery is decreased.Atherosclerosis is the most common cause of ischemic heart disease andis of great medical importance since the occlusion of medium andlarge-sized arteries diminishes the supply of blood to vital organs suchas the heart muscles and the brain. The sequelae to atherosclerosisinclude ischemic heart disease, heart failure, life-threateningarrythmias, senility, and stroke.

The fact that cholesterol is a major component of atheroscleroticlesions or plaques has been known for more than 100 years. Variousresearchers have studied the role of cholesterol in lesion formation anddevelopment and also, more importantly, whether lesion formation can beprevented or lesion development arrested or reversed. Atheromatouslesions have now been shown [Adams, et al., Atherosclerosis, 13, 429(1974)] to contain a greater quantity of esterified as opposed tounesterified cholesterol than the surrounding undiseased arterial wall.The intracellular esterification of cholesterol with fatty acids iscatalyzed by the enzyme Fatty acyl CoA:cholesterol acyl transferase orACAT and the accumulation and storage of cholesteryl esters in thearterial wall is associated with increased activity of this enzyme[Hashimoto and Dayton, Atherosclerosis, 28, 447 (1977)]. In addition,cholesteryl esters are removed from cells at a slower rate thanunesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15,273 (1972) and 22, 379 (1975)]. Thus, inhibition of the ACAT enzymewould diminish the rate of cholesterol esterification, decrease theaccumulation and storage of cholesteryl esters in the arterial wall, andprevent or inhibit the formation and developoment of atheromatouslesions. The compounds of the present invention are very potentinhibitors of the ACAT enzyme. Thus, these compounds are useful forcontrolling and reducing the cholesteryl ester content of mammalianarterial walls, and decreasing the accumulation and storage ofcholesterol in the arterial walls of mammals. Further, the compounds ofthis invention inhibit the formation or development of atheroscleroticlesions in mammals.

The evidence that hyperlipidemia is one of the factors involved incoronary heart disease is very impressive. A most important studycarried out in Framingham, Mass. (Gordon and Verter, 1969) in over 5,000persons for more than 12 years established a correlation between highconcentrations of blood cholesterol and increased risk of heart attack.Although the causes of coronary artery disease are multiple, one of themost constant factors has been the elevated concentration of lipids inthe blood plasma. A combined elevation of cholesterol and triglycerideshas been shown (Carlson and Bottiger, 1972) to carry the highest risk ofcoronary heart disease. The majority of patients with ischemic heartdisease or peripheral vascular disease were found to havehyperlipoproteinemia, involving very low-density and/or low-densitylipoproteins (Lewis, et al., 1974).

We have now found that certain members of this class of compounds cansafely and effectively lower both serum lipids in warm-blooded animals.Such action on serum lipids is considered to be very useful in thetreatment of atherosclerosis. For some time it has been considereddesirable to lower serum-lipid levels and to correct lipoproteinimbalance in mammals as a preventive measure against atherosclerosis.The compounds of the present invention do not act by blocking latestages of cholesterol biosynthesis and thus do not produce accumulationof intermediates such as desmosterol, as equally undesirable ascholesterol itself. Compounds with the combination of therapeuticallyfavorable characteristics possessed by those of the present inventioncan be safely administered to warm-blooded mammals for the treatment ofhyperlipidemic and atherosclerotic states found in patients with orprone to heart attacks, to peripheral or cerebral vascular disease andto stroke.

The compounds of this invention exhibit antiatherosclerotic activity andthe invention should not be construed as limited to any particularmechanism of antiatherosclerotic action.

SUMMARY OF THE INVENTION

This invention relates to new tetrasubstituted urea and thioureacompounds, their preparation, pharmaceutical compositions containingthem, and their use in the treatment of atherosclerosis. Moreparticularly, it is concerned with ureas and thioureas which may berepresented by formula I: ##STR1## wherein X represents at least onesubstituent selected from the group consisting of hydrogen, C₁ -C₄alkyl, C₁ -C₄ alkenyl, C₁ -C₄ alkynyl, hydroxy, C₁ -C₄ alkoxy, phenoxy,mercapto, C₁ -C₄ alkylthio, amino, C₁ -C₄ alkylamino, di-(C₁ -C₄alkyl)amino, halo, trihalomethyl, C₁ -C₄ alkanoyl, benzoyl, C₁ -C₄alkanamido, C₁ -C₄ alkanesulfonyl, C₁ -C₄ alkanesulfinyl,benzenesulfonyl, toluenesulfonyl, nitro, cyano, carboxy, C₁ -C₄carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl,ortho-phenylene, tolyl, benzyl, halobenzyl, methylbenzyl and the group##STR2## wherein Y is selected from the group consisting of oxygen andsulfur; R₁ and R₂ are the same or different and are independentlyselected from the group consisting of C₄ -C₁₂ alkyl, C₄ -C₁₂ alkenyl, C₄-C₁₂ alkynyl, C₄ -C₁₂ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₇ -C₁₄aralkyl, and C₇ -C₁₄ aralkyl in which an aromatic ring bears at leastone substituent selected from the group consisting of C₁ -C₁₀ alkyl, C₁-C₁₀ alkoxy, phenoxy, benzyloxy, methylenedioxy, C₁ -C₁₄ alkylthio,phenyl, halo, trihalomethyl, adamantyl, C₁ -C₄ carboalkoxy, and nitro;R₃ is selected from the group consisting of C₁ -C₄ alkyl, C₁ -C₄alkenyl, C₁ -C₄ alkynyl, benzyl, benzyl bearing at least one substituentZ, naphthyl, phenyl and phenyl bearing at least one substituent Z, Zbeing selected independently of X from the group consisting of thosefrom which X is selected.

Preferred embodiments of the invention are those in which Y is oxygen.More preferred are those in which X represents at least one C₁ -C₄ alkylor halo substituent and R₁ and R₂ are the same or different and areindependently selected from the group consisting of C₄ -C₁₂ alkyl, C₇-C₁₄ aralkyl and substituted C₇ -C₁₄ aralkyl. The most preferred arethose in which X represents at least one methyl or chloro substituentand Z is hydrogen, methyl or chloro.

Preferred specific embodiments involve:

1,1-dibenzyl-3-(2,4-dimethylphenyl)-3-phenylurea

1,1-dibenzyl-3-(3-chloro-4-methylphenyl)-3-phenylurea

1,1-di-(n-butyl)-3-(2,4-dimethylphenyl)-3-phenylurea

1,1-di-(n-butyl)-3-(3-chloro-4-methylphenyl)-3-phenylurea

1,1-dibenzyl-3,3-di-(2,4-dimethylphenyl)urea

1,1-dibenzyl-3,3-di-(3-chloro-4-methylphenyl)urea

1,1-di-(n-butyl)-3,3-di-(2,4-dimethylphenyl)urea

1,1-di-(n-butyl)-3,3-di-(3-chloro-4-methylphenyl)urea

1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)-3-phenylurea

1-benzyl-1-(n-butyl)-3-(3-chloro-4-methylphenyl)-3-phenylurea

1-benzyl-1-(n-butyl)-3,3-di-(2,4-dimethylphenyl)urea

1-benzyl-1-(n-butyl)-3,3-di-(3-chloro-methylphenyl)urea

This invention also relates to a method of reducing the cholesterolcontent of the arterial walls of mammals which comprises administeringto said mammal an effective amount of a compound as recited above.

This invention also relates to a method of treating hyperlipidemia inmammals which comprises administering to said mammal an effective amountof a compound as recited above.

This invention further relates to a method of inhibiting atheroscleroticlesion development in mammals which comprises administering to saidmammal an effective amount of a compound as recited above.

This invention still further relates to a pharmaceutical compositionwhich comprises and effective antiatherosclerotic amount of a compoundas recited above in association with a pharmaceutically acceptablecarrier.

Finally, this invention relates to processes for preparing compounds asrecited above. One process useful for the preparation of thetetrasubstituted ureas and thioureas of this invention involves reactinga compound of formula II; wherein A and B are leaving groups, which maybe the same or different, selected from the group consisting of halo, C₁-C₄ alkoxy, C₁ -C₄ alkylthiophenoxy, 4-chlorophenoxy and 4-nitrophenoxy;with a secondary amine of formula III to yield an intermediate offormula IV and then reacting the intermediate with an arylamine offormula V, wherein X, Y, R₁, R₂ and R₃ are as defined above. ##STR3##

A second process for the preparation of tetrasubstituted ureas andthioureas involves reacting a compound of formula II with an arylamineof formula V to yield an intermediate of formula VI; wherein X, Y and R₃are as defined above and then reacting the intermediate with a secondaryamine of formula III; wherein R₁ and R₂ are as defined above. ##STR4##

DETAILED DESCRIPTION OF THE INVENTION

Certain of the novel ureas and thioureas of this invention are preparedby reacting activated derivatives of carbonic acid such as phosgene,thiophosgene, or phenyl chloroformate with secondary amines to yield anintermediate, for instance, a disubstituted carbamyl chloride. Thisintermediate is in turn reacted with an arylamine to yield the urea orthiourea. The preparation of the intermediate is conducted in an aproticsolvent such as tetrahydrofuran, toluene, xylene, or the like attemperatures from about room temperature up to the boiling point of thesolvent. The intermediate may be isolated by evaporation and purified bydistillation if necessary. The intermediate is then reacted with anarylamine in an aprotic solvent such as dimethylacetamide in thepresence of a base such as sodium hydride at temperatures from aboutroom temperature up to the boiling point of the solvent used. An exampleof this process is the reaction of phosgene with N-benzyl-n-butylaminein toluene to yield the intermediate N-benzyl-N-(n-butyl)carbamylchloride, which is then reacted with diphenylamine inN,N-dimethylacetamide in the presence of sodium hydride to yield1-benzyl-1-(n-butyl)-3,3-diphenylurea.

Other of the novel ureas and thioureas of this invention are prepared byreacting arylamines with activated derivatives of carbonic acid such asphosgene or thiophosgene to yield an intermediate, for instance, anarylcarbamyl chloride. This intermediate is then reacted with asecondary amine to yield the urea or thiourea. The preparation of thisintermediate is conducted in an aprotic solvent such as toluene orxylene at temperatures from about room temperature up to the boilingpoint of the solvent in the presence of a base, for example,N,N-dimethylaniline. The intermediate is then reacted with a secondaryamine in an aprotic solvent such as toluene at temperatures from roomtemperature or below up to the boiling point of the solvent. An exampleof this process is the reaction of phosgene withN-phenyl-3-chloroaniline to yield the intermediateN-(3-chlorophenyl)-N-phenyl carbamyl chloride which is then reacted withN-benzyl-n-butylamine to yield1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea.

The ureas and thioureas of this invention which contain carboxy groupsare prepared by alkaline hydrolysis of the corresponding carboalkoxyureas and thioureas, prepared by the synthetic methods described above.Likewise, those which contain hydroxy, mercapto, or amino groups areprepared by alkaline hydrolysis of the corresponding O-acetyl, S-acetyland N-acetyl ureas and thioureas, respectively, the latter also havingbeen obtained by the urea and thiourea syntheses described above.Alternatively, ureas and thioureas containing hydroxy groups areprepared by cleavage of the corresponding methoxy compounds using Lewisacids such as boron tribromide.

Certain substituted N-benzylanilines which are intermediates requiredfor the synthesis of some of the novel tetrasubstituted ureas andthioureas of this invention are not known in the art. The requisiteN-benzylanilines are prepared by reactions of various benzaldehydes withanilines to yield anils. The anils are then reduced to yield thesubstituted N-benzylanilines. An example of such a synthesis involvesthe reaction of 2,4-dimethylbenzaldehyde with 2,4-dichloroaniline toyield N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline followed byreduction with sodium borohydride to yieldN-(2,4-dimethylbenzyl)-2,4-dichloroaniline.

The ureas and thioureas of the present invention are obtained ascrystalline solids or distillable liquids. They are characterized bydistinct melting or boiling points and unique spectra. They areappreciably soluble in organic solvents but generally less soluble inwater. Those compounds which contain carboxylic acid groups may beconverted to their alkali metal and alkaline earth salts by treatmentwith the appropriate metal hydroxides and those which contain aminogroups may be converted to their ammonium salts by treatment withorganic or mineral acids. Both of these types of salts exhibit increasedwater solubility.

The preparation and properties of the compounds of this invention willbe described in greater detail in conjunction with the specific examplesshown below.

The compounds of the present invention were assayed for two types ofbiological activity related to their potential use asantiatherosclerotic agents. Compounds were tested in vitro for theirability to inhibit the enzyme fatty acyl CoA:cholesterol acyltransferase (ACAT) and in vivo for serum hypolipidemic activity asmeasured by their ability to inhibit lipid absorption in rats. Thecompounds were tested for their ability to inhibit ACAT according to thefollowing procedure:

Rat adrenals were homogenized in 0.2M monobasic potassium phosphatebuffer, pH 7.4, and centrifuged at 1000 times gravity for 15 minutes at5° C. The supernatant, containing the microsomal fraction, served as thesource of the cholesterol-esterifying enzyme, fatty acyl CoA:cholesterolacyl transferase (ACAT). A mixture comprising 50 parts of adrenalsupernatant, 10 parts of albumin (BSA) (50 mg./ml.), 3 parts of testcompound (final concentration 5.2 g./ml.) and 500 parts of buffer waspreincubated at 37° C. for 10 minutes. After treatment with 20 parts ofoleoyl CoA(¹⁴ C-0.4 Ci) the mixture was incubated at 37° C. for 10minutes. A control mixture, omitting the test compound, was prepared andtreated in the same manner. The lipids from the incubation mixture wereextracted into an organic solvent and separated by thin-layerchromatography. The cholesteryl ester fraction was counted in ascintillation counter. This procedure is a modification of thatdescribed by Hashimoto, et al., Life Scie., 12 (Part II), 1-12 (1973).

The results of this test on representative compounds of this inventionappear in Table I.

                  TABLE I                                                         ______________________________________                                        Compound                % Inhibition                                          ______________________________________                                        1-Benzyl-1-(n-butyl)-3,3-diphenylurea                                                                 75.9                                                  1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-                                                            72.3                                                  phenylurea                                                                    1-Benzyl-1-(n-butyl)-3-(2-naphthyl)-3-                                                                83.6                                                  phenylurea                                                                    1-Benzyl-1-(n-butyl)-3-benzyl-3-phenylurea                                                            81.8                                                  1-Benzyl-1-(n-butyl)-3-(3-methylphenyl)-3-                                                            82.0                                                  phenylurea                                                                    1-Benzyl-1-(n-butyl)-3-(3-methoxyphenyl)-3-                                                           82.5                                                  phenylurea                                                                    1-Benzyl-1-(n-butyl)-3-(4-isopropoxyphenyl)-3-                                                        77.8                                                  phenylurea                                                                    1-Benzyl-1-(n-butyl)-3-(1-naphthyl)-3-phenyl-                                                         76.3                                                  urea                                                                          1-Benzyl-1-(n-butyl)-3-(2-naphthyl)-3-(3-                                                             82.7                                                  chlorophenyl)urea                                                             1-Benzyl-1-(n-butyl)-3,3-di-(2-naphthyl)urea                                                          93.2                                                  1,3-Dibenzyl-1,3-di-(n-butyl)urea                                                                     95.4                                                  ______________________________________                                    

Inhibition of cholesterol absorption was determined by feeding maleSprague-Dawley rats, weighing 150-170 g., a 1% cholesterol: 0.5% cholicacid diet for 2 weeks. The diet was contained compounds being tested ata dose of 0.03% of the diet. Control rats were fed the same diet withoutany compound. At the end of the test, the rats were sacrificed bydecapitation. Blood is collected, centrifuged at 1.5 kg times gravityfor 10 minutes at 4° C., and the serum is then analyzed for cholesteroland triglycerides enzymatically by the method of Trinder, P., Analyst,77, 321 (1952) on a Centrifichem 400 Analyzer. Livers are removed, a 0.4g sample is taken from the center of the large lobe, and the sample issubjected to saponification using 25% saturated potassium hydroxide inethanol. The resulting neutral sterols are extracted with petroleumether and extract analyzed for cholesterol. The effectiveness of thecompound in inhibiting cholesterol absorption is measured by thelowering of either serum cholesterol or liver cholesterol relative thevalues for control rats.

The results of this test on a typical compound of this invention appearin Table II.

                  TABLE II                                                        ______________________________________                                        Compound                 Result                                               ______________________________________                                        1-Benzyl-1-(n-butyl)-3-(3-methoxyphenyl)-3-                                                            Active                                               phenylurea                                                                    ______________________________________                                    

The tests reported or shown in Tables I-II, inclusive, have beenactually carried out and the results therein actually obtained orconcluded therefrom.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, dilutents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, suspensionscontaining, for example, from about 0.5 to 5% of suspending agent,syrups containing, for example from about 10 to 50% of sugar, andelixirs containing, for example, from about 20 to 50% ethanol, and thelike, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5 to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5 and 60% by weight.

The antiatherosclerotic effective dosage of active ingredient employedmay vary depending on the particular compound employed, the mode ofadministration and the severity of the condition being treated. However,in general, satisfactory results are obtained when the compounds of theinvention are administered at a daily dosage of from about 2 mg. toabout 500 mg./kg. of animal body weight, preferably given in divideddoses two to four times a day, or in sustained release form. For mostlarge mammals, the total daily dosage is from about 100 mg. to about5,000 mg. preferably from about 100 mg. to 2,000 mg. Dosage formssuitable for internal use comprise from about 25 to 500 mg. of theactive compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier. This dosage regimen may be adjustedto provide the optimal therapeutic response. For example, severaldivided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. A decided practical advantage is that these active compoundsmay be administered orally as well as by intravenous, intramuscular, orsubcutaneous routes if necessary. Solid carriers include starch,lactose, dicalcium phosphate, microcrystalline cellulose, sucrose andkaolin, while liquid carriers include sterile water, polyethyleneglycols, non-ionic surfactants and edible oils such as corn, peanut andsesame oils, as are appropriate to the nature of the active ingredientand the particular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHTand BHA.

The preferred pharmaceutical compositions from the stand-point of easeof preparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be filledto the extent that easy syringability exists. It must be stable underthe conditions of manufacture and storage and must be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

EXAMPLE 1 1-Benzyl-1-(n-butyl)-3,3-diphenylurea

A solution of 20.0 g of phosgene in 100 ml. of toluene is stirred at 0°C. while a solution of 32.6 g. of N-benzyl-n-butylamine in 50 ml. oftoluene is added during 15 minutes. The mixture is filtered and thefiltrate is evpaorated. The residue is evaporatively distilled at 105°C. under reduced pressure (250-350 microns) to yieldN-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.

A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide isadded during one hour to a stirred mixture of 5.19 g. ofN-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and65 ml. of dimethylacetamide under a nitrogen atmosphere at 45°-50° C.The mixture is stirred for 2 hours at 50° C. and then poured into water.The mixture is extracted with methylene chloride and the extract isevaporated. The residue is purified by chromatography using silica gelas the adsorbant and acetone-hexane as the eluent. After evaporation ofthe eluent, the residue is evaporatively distilled at 165° C. underreduced pressure (150 microns) to yield1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, clorlessliquid.

EXAMPLE 2 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea

A solution of 5.09 g. of N-phenyl-3-chloraniline in 20 ml. of toluene isadded to a solution of 4.70 g. of phosgene and 3.64 g. ofN,N-dimethylaniline in 55 ml. of toluene and the mixture is warmed to400° C. and then stirred while cooling to room temperature during 45minutes. The mixture is extracted with water and the organic layer isseparateld and evaporated to about one-half its volume. To this solutionis added 100 ml. of toluene followed by 9.80 g. ofN-benzyl-n-butylamine. The resulting mixture is sitrred under reflux for30 minutes and then washed with water, 1N hydrochloric acid, andsaturated sodium bicarbonate solution. The organic layer is separated,dried over sodium sulfate, decolorized using activated charcoal, andevaporated. The residue is evaporatively distilled at 185°-190° C. underreduced pressure (105 microns) to yield1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea as a viscous,pale-yellow liquid.

With reference to Examples 1 and 2 and Table III, only Examples 1-5; 9;18; 40; 43; 99-100; 150-160; and 168 inclusive, have been actuallycarried out. Those compounds of the other actual Examples in Table IIIwere prepared from the appropriate amines using phosgene or thiophosgeneby the methods of Examples 1 and 2. All other Examples are simulated orpredicted.

                                      TABLE III                                   __________________________________________________________________________    Ex. Compound                         Melting Point                            __________________________________________________________________________    3   1,3-Dibenzyl-1-(n-butyl)-3-phenylurea                                                                          yellow oil                               4   1-Benzyl-1-(n-butyl)-3-(2-naphthyl)-3-phenylurea                                                               orange oil                               5   1-Benzyl-1-(n-butyl)-3-(3-methylphenyl)-3-phenylurea                                                           oil                                      6   1-Benzyl-1-(n-butyl)-3-(4-methylphenyl)-3-phenylurea                      7   1-Benzyl-1-(n-butyl)-3-(3-ethylphenyl)-3-phenylurea                       8   1-Benzyl-1-(n-butyl)-3-(4-ethylphenyl)-3-phenylurea                       9   1-Benzyl-1-(n-butyl)-3-(4-isopropylphenyl)-3-phenylurea                                                        amber oil                                10  1-Benzyl-1-(n-butyl)-3-(4-n-butylphenyl)-3-phenylurea                     11  1-Benzyl-1-(n-butyl)-3-(2,3-dimethylphenyl)-3-phenylurea                  12  1-Benzyl-1-(n-butyl)-3-(2,5-dimethylphenyl)-3-phenylurea                  13  1-Benzyl-1-(n-butyl)-3-(2,6-dimethylphenyl)-3-phenylurea                  14  1-Benzyl-1-(n-butyl)-3-(3,4-dimethylphenyl)-3-phenylurea                  15  1-Benzyl-1-(n-butyl)-3-(3,5-dimethylphenyl)-3-phenylurea                  16  1-Benzyl-1-(n-butyl)-3-(2,4,5-trimethylphenyl)-3-phenylurea               17  1-Benzyl-1-(n-butyl)-3-(2,4,6-trimethylphenyl)-3-phenylurea               18  1-Benzyl-1-(n-butyl)-3-(3-methoxyphenyl)-3-phenylurea                                                          amber oil                                19  1-Benzyl-1-(n-butyl)-3-(4-n-butoxyphenyl)-3-phenylurea                    20  1-Benzyl-1-(n-butyl)-3-(2,4-dimethoxyphenyl)-3-phenylurea                 21  1-Benzyl-1-(n-butyl)-3-(4-methylthiophenyl)-3-phenylurea                  22  1-Benzyl-1-(n-butyl)-3-(2-chlorophenyl)-3-phenylurea                      23  1-Benzyl-1-(n-butyl)-3-(4-chlorophenyl)-3-phenylurea                      24  1-Benzyl-1-(n-butyl)-3-(2-bromophenyl)-3-phenylurea                       25  1-Benzyl-1-(n-butyl)-3-(4-bromophenyl)-3-phenylurea                       26  1-Benzyl-1-(n-butyl)-3-(4-fluorophenyl)-3-phenylurea                      27  1-Benzyl-1-(n-butyl)-3-(4-iodophenyl)-3-phenylurea                        28  1-Benzyl-1-(n-butyl)-3-(2,3-dichlorophenyl)-3-phenylurea                  29  1-Benzyl-1-(n-butyl)-3-(2,4-dichlorophenyl)-3-phenylurea                  30  1-Benzyl-1-(n-butyl)-3-(2,5-dichlorophenyl)-3-phenylurea                  31  1-Benzyl-1-(n-butyl)-3-(3,5-dichlorophenyl)-3-phenylurea                  32  1-Benzyl-1-(n-butyl)-3-(2,4,6-trichlorophenyl)-3-phenylurea               33  1-Benzyl-1-(n-butyl)-3-(2,4-difluorophenyl)-3-phenylurea                  34  1-Benzyl-1-(n-butyl)-3-(3-trifluoromethylphenyl)-3-phenylurea             35  1-Benzyl-1-(n-butyl)-3-(3-acetylphenyl)-3-phenylurea                      36  1-Benzyl-1-(n-butyl)-3-(4-acetylphenyl)-3-phenylurea                      37  1-Benzyl-1-(n-butyl)-3-(4-carboethoxyphenyl)-3-phenylurea                 38  1-Benzyl-1-(n-butyl)-3-(4-phenoxyphenyl)-3-phenylurea                     39  1-Benzyl-1-(n-butyl)-3-(2-cyanophenyl)-3-phenylurea                       40  1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-(2-naphthyl)urea                                                     yellow oil                               41  1-Benzyl-1-(n-butyl)-3-(3-chloro-4-methylphenyl)-3-phenylurea             42  1-Benzyl-1-(n-butyl)-3-(2,6-dibromo-4-fluorophenyl)-3-phenylurea          43  1-Benzyl-1-(n-butyl)-3-(1-naphthyl)-3-phenylurea                                                               amber oil                                44  1-Benzyl-1-(n-butyl)-3-(2-chloro-4-nitrophenyl)-3-phenylurea              45  1-Benzyl-1-(n-butyl)-3-(4-chloro-3-trifluoromethylphenyl)-3-phenylurea        2                                                                         46  1-Benzyl-1-(n-butyl)-3-(4-chloro-2-trifluoromethylphenyl)-3-phenylurea        4                                                                         47  1-Benzyl-1-(n-butyl)-3-(2-chloro-5-trifluoromethylphenyl)-3-phenylurea        9                                                                         48  1-Benzyl-1-(n-butyl)-3-(3,4-methylenedioxyphenyl)-3-phenylurea            49  1-Benzyl-1-(n-butyl)-3-(4-phenylphenyl)-3-phenylurea                      50  1-Benzyl-1-(n-butyl)-3-(4-benzylphenyl)-3-phenylurea                      51  1-Benzyl-1-(n-undecyl)-3-(2,4-dimethylphenyl)-3-phenylurea                52  1-Benzyl-1-(2-phenylethyl)-3-(2,4-dimethylphenyl)-3-phenylurea            53  1-Benzyl-1-(n-butyl)-3,3-di(2-methylphenyl)urea                           54  1-Benzyl-1-(n-butyl)-3,3-di(3-methylphenyl)urea                           55  1-Benzyl-1-(n-butyl)-3,3-di(4-methylphenyl)urea                           56  1-Benzyl-1-(n-butyl)-3,3-di(3-ethylphenyl)urea                            57  1-Benzyl-1-(n-butyl)-3,3-di(4-ethylphenyl)urea                            58  1-Benzyl-1-(n-butyl)-3,3-di(4-isopropylphenyl)urea                        59  1-Benzyl-1-(n-butyl)-3,3-di(4-n-butylphenyl)urea                          60  1-Benzyl-1-(n-butyl)-3,3-di(2,3-dimethylphenyl)urea                       61  1-Benzyl-1-(n-butyl)-3,3-di(2,5-dimethylphenyl)urea                       62  1-Benzyl-1-(n-butyl)-3,3-di(2,6-dimethylphenyl)urea                       63  1-Benzyl-1-(n-butyl)-3,3-di(3,4-dimethylphenyl)urea                       64  1-Benzyl-1-(n-butyl)-3,3-di(3,5-dimethylphenyl)urea                       65  1-Benzyl-1-(n-butyl)-3,3-di(2,4,5-trimethylphenyl)urea                    66  1-Benzyl-1-(n-butyl)-3,3-di(2,4,6-trimethylphenyl)urea                    67  1-Benzyl-1-(n-butyl)-3,3-di(4-methoxyphenyl)urea                          68  1-Benzyl-1-(n-butyl)-3,3-di(4-n-butoxyphenyl)urea                         69  1-Benzyl-1-(n-butyl)-3,3-di(2,4-dimethoxyphenyl)urea                      70  1-Benzyl-1-(n-butyl)-3,3-di(4-methylthiophenyl)urea                       71  1-Benzyl-1-(n-butyl)-3,3-di(2-chlorophenyl)urea                           72  1-Benzyl-1-(n-butyl)-3,3-di(3-chlorophenyl)urea                           73  1-Benzyl-1-(n-butyl)-3,3-di(4-chlorophenyl)urea                           74  1-Benzyl-1-(n-butyl)-3,3-di(2-bromophenyl)urea                            75  1-Benzyl-1-(n-butyl)-3,3-di(4-bromophenyl)urea                            76  1-Benzyl-1-(n-butyl)-3,3-di(4-fluorophenyl)urea                           77  1-Benzyl-1-(n-butyl)-3,3-di(4-iodophenyl)urea                             78  1-Benzyl-1-(n-butyl)-3,3-di(2,3-dichlorophenyl)urea                       79  1-Benzyl-1-(n-butyl)-3,3-di(2,4-dichlorophenyl)urea                       80  1-Benzyl-1-(n-butyl)-3,3-di(2,5-dichlorophenyl)urea                       81  1-Benzyl-1-(n-butyl)-3,3-di(3,5-dichlorophenyl)urea                       82  1-Benzyl-1-(n-butyl)-3,3-di(2,4,6-trichlorophenyl)urea                    83  1-Benzyl-1-(n-butyl)-3,3-di(2,4-difluorophenyl)urea                       84  1-Benzyl-1-(n-butyl)-3,3-di(3-trifluoromethylphenyl)urea                  85  1-Benzyl-1-(n-butyl)-3,3-di(3-acetylphenyl)urea                           86  1-Benzyl-1-(n-butyl)-3,3-di(4-acetylphenyl)urea                           87  1-Benzyl-1-(n-butyl)-3,3-di(4-carboethoxyphenyl)urea                      88  1-Benzyl-1-(n-butyl)-3,3-di(4-phenoxyphenyl)urea                          89  1-Benzyl-1-(n-butyl)-3,3-di(2-cyanophenyl)urea                            90  1-Benzyl-1-(n-butyl)-3,3-di(3-chloro-2-methylphenyl)urea                  91  1-Benzyl-1-(n-butyl)-3,3-di(3-chloro-4-methylphenyl)urea                  92  1-Benzyl-1-(n-butyl)-3,3-di(2,6-dibromo-4-fluorophenyl)urea               93  1-Benzyl-1-(n-butyl)-3,3-di(2-nitro-4-methylphenyl)urea                   94  1-Benzyl-1-(n-butyl)-3,3-di(2-chloro-4-nitrophenyl)urea                   95  1-Benzyl-1-(n-butyl)-3,3-di(4-chloro-3-trifluoromethylphenyl)urea         96  1-Benzyl-1-(n-butyl)-3,3-di(4-chloro-2-trifluoromethylphenyl)urea         97  1-Benzyl-1-(n-butyl)-3,3-di(2-chloro-5-trifluoromethylphenyl)urea         98  1-Benzyl-1-(n-butyl)-3,3-di(3,4-methylenedioxyphenyl)urea                 99  1-Benzyl-1-(n-butyl)-3,3-dibenzylurea                                                                          yellow oil                               100 1-Benzyl-1-(n-butyl)-3,3-di(2-naphthyl)urea                                                                    amber oil                                101 1-Benzyl-1-(n-butyl)-3,3-diphenylthiourea                                 102 1-Benzyl-1-(n-hexadecyl)-3,3-diphenylthiourea                             103 1-Benzyl-1-(n-butyl)-3-(2-methylphenyl)-3-phenylthiourea                  104 1-Benzyl-1-(n-butyl)-3-(3-methylphenyl)-3-phenylthiourea                  105 1-Benzyl-1-(n-butyl)-3-(4-methylphenyl)-3-phenylthiourea                  106 1-Benzyl-1-(n-butyl)-3-(3-ethylphenyl)-3-phenylthiourea                   107 1-Benzyl-1-(n-butyl)-3-(4-ethylphenyl)-3-phenylthiourea                   108 1-Benzyl-1-(n-butyl)-3-(4-isopropylphenyl)-3-phenylthiourea               109 1-Benzyl-1-(n-butyl)-3-(4-n-butylphenyl)-3-phenylthiourea                 110 1-Benzyl-1-(n-butyl)-3-(2,3-dimethylphenyl)-3-phenylthiourea              111 1-Benzyl-1-(n-butyl)-3-(2,5-dimethylphenyl)-3-phenylthiourea              112 1-Benzyl-1-(n-butyl)-3-(2,6-dimethylphenyl)-3-phenylthiourea              113 1-Benzyl-1-(n-butyl)-3-(3,4-dimethylphenyl)-3-phenylthiourea              114 1-Benzyl-1-(n-butyl)-3-(3,5-dimethylphenyl)-3-phenylthiourea              115 1-Benzyl-1-(n-butyl)-3-(2,4,5-trimethylphenyl)-3-phenylthiourea           116 1-Benzyl-1-(n-butyl)-3-(2,4,6-trimethylphenyl)-3-phenylthiourea           117 1-Benzyl-1-(n-butyl)-3-(4-methoxyphenyl)-3-phenylthiourea                 118 1-Benzyl-1-(n-butyl)-3-(4-n-butoxyphenyl)-3-phenylthiourea                119 1-Benzyl-1-(n-butyl)-3-(2,4-dimethoxyphenyl)-3-phenylthiourea             120 1-Benzyl-1-(n-butyl)-3-(4-methylthiophenyl)-3-phenylthiourea              121 1-Benzyl-1-(n-butyl)-3-(2-chlorophenyl)-3-phenylthiourea                  122 1-Benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylthiourea                  123 1-Benzyl-1-(n-butyl)-3,3-di(2-methylphenyl)thiourea                       124 1-Benzyl-1-(n-butyl)-3,3-di(3-methylphenyl)thiourea                       125 1-Benzyl-1-(n-butyl)-3,3-di(4-methylphenyl)thiourea                       126 1-Benzyl-1-(n-butyl)-3,3-di(3-ethylphenyl)thiourea                        127 1 Benzyl-1-(n-butyl)-3,3-di(4-ethylphenyl)thiourea                        128 1-Benzyl-1-(n-butyl)-3,3-di(4-isopropylphenyl)thiourea                    129 1-Benzyl-1-(n-butyl)-1,1-di(4-n-butylphenyl)thiourea                      130 1-Benzyl-1-(n-butyl)-1,1-di(1,2-dimethylphenyl)thiourea                   131 1-Benzyl-1-(n-butyl)-1,1-di(2,5-dimethylphenyl)thiourea                   132 1-Benzyl-1-(n-butyl)-1,1-di(2,6-dimethylphenyl)thiourea                   133 1-Benzyl-1-(n-butyl)-1,1-di(1,4-dimethylphenyl)thiourea                   134 1-Benzyl-1-(n-butyl)-1,1-di(1,5-dimethylphenyl)thiourea                   135 1-Benzyl-1-(n-butyl)-1,1-di(2,4,5-trimethylphenyl)thiourea                136 1-Benzyl-1-(n-butyl)-1,1-di(2,4,6-trimethylphenyl)thiourea                137 1-Benzyl-1-(n-butyl)-1,1-di(4-methoxyphenyl)thiourea                      138 1-Benzyl-1-(n-butyl)-1,1-di(4-n-butoxyphenyl)thiourea                     139 1-Benzyl-1-(n-butyl)-1,1-di(2,4-dimethoxyphenyl)thiourea                  140 1-Benzyl-1-(n-butyl)-1,1-di(4-methylthiophenyl)thiourea                   141 1-Benzyl-1-(n-butyl)-1,1-di(chlorophenyl)thiourea                         142 1,1-Dibenzyl-3-(2,4-dimethylphenyl)-3-phenylurea                          143 1,1-Dibenzyl-3-(3-chloro-4-dimethylphenyl)-3-phenylurea                   144 1,1-Di-(n-butyl)-3-(2,4-dimethylphenyl)-3-phenylurea                      145 1,1-Di-(n-butyl)-3-(3-chloro-4-dimethylphenyl)-3-phenylurea               146 1,1-Dibenzyl-3,3-di(2,4-dimethylphenyl)urea                               147 1,1-Dibenzyl-3,3-di(3-chloro-4-dimethylphenyl)urea                        148 1,1-Di-(n-butyl)-3,3-di(2,4-dimethylphenyl)urea                           149 1,1-Di-(n-butyl)-3,3-di(3-chloro-4-dimethylphenyl)urea                    150 1-Benzyl-1-(n-butyl)-3-benzyl-3-(4-chlorophenyl)urea                                                           oil                                      151 1-Bnezyl-1-(n-butyl)-3-benzyl-3-(2,4-dimethylphenyl)urea                                                       oil                                      152 1-Benzyl-1-(n-butyl)-3-benzyl-3-(2,4-dichlorophenyl)urea                                                       oil                                      153 1-Benzyl-1-(n-butyl)-3-(3-nitrobenzyl)-3-(3,5-dimethoxy-                                                       oil                                          phenyl)urea                                                               154 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylbenzyl)-3-(2,4-di-                                                         oil                                          methylphenyl)urea                                                         155 1-Benzyl-1-(n-butyl)-3-(2,4-dichlorobenzyl)-3-(2,4-dichloro-                                                   oil                                          phenyl)urea                                                               156 1-Benzyl-1-(n-butyl)-3-(2-chlorobenzyl)-3-(2-chlorophenyl)urea                                                 oil                                      157 1-Benzyl-1-(n-butyl)-3-(4-methylphenyl)-3-(4-methylbenzyl)urea                                                 oil                                      158 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylbenzyl)-3-(2,4-dichloro                                                    oil                                          phenyl)urea                                                               159 1-Benzyl-1-(n-butyl)-3-(2,4-dichlorobenzyl)-3-(2,4-dimethyl-                                                   oil                                          phenyl)urea                                                               160 1-Benzyl-1-(n-butyl)-3-(3-chloro-4-methylbenzyl)-3-(4-methyl-                                                  oil                                          phenyl)urea                                                               161 1-Benzyl-1-(n-butyl)-3-(2,4-dimethylbenzyl)-3-phenyl                                                           oila                                     162 1-Benzyl-1-(n-butyl)-3-[3,5-di(trifluoromethyl)benzyl]-3-                                                      oil                                          phenyl urea                                                               163 1-Benzyl-1-(n-butyl)-3-(3-aminobenzyl)-3-)(3,5-dimethoxyphenyl)                                                156-158°                              urea picrate                                                              164 1-Benzyl-1-(n-butyl)-3-benzyl-3-(3-aminophenyl)urea                                                            96-98°                            165 1-Benzyl-1-(n-butyl)-3-benzyl-3-(2,4,6-trimethylphenyl)urea                                                    63-69°                            166 1-Benzyl-1-(n-butyl)-3-benzyl-3-(3-nitrophenyl)urea                                                            yellow oil                               167 1-Benzyl-1-(n-butyl)-3-(4-benzyloxybenzyl)-3-(4-carbo-                        ethoxyphenyl)urea                                                         168 1-Benzyl-1-(n-butyl)-3-benzyl-3-(3-acetamidophenyl)urea                                                        oil                                      169 1-Benzyl-1,3-di-(n-butyl)-3-phenylurea                                    170 1-Benzyl-1-(n-butyl)-3-(n-hexyl)-3-phenyl urea                            171 1-Benzyl-1-(n-butyl)-3-(n-pentyl)-3-(2,4-dimethylphenyl)urea              172 1-Benzyl-1-(n-heptyl)-3-(n-octyl)-3-(2,4-dimethylphenyl)urea              173 1-Benzyl-1-(n-hexyl)-3-(n-butyl)-3-(3-chloro-4-methylphenyl)                  urea                                                                      174 1-(4-chlorobenzyl)-1-(4-methylbenzyl)-3-(n-hexyl)-3-(2,4-di-                  methylphenyl)urea                                                         __________________________________________________________________________

EXAMPLE 175 N-(2,4-Dimethylbenzylidene)-2,4-dichloroaniline

A mixture of 26.8 g. of 2,4-dimethylbenzaldehyde, 32.4 g. of2,4-dichloroaniline, 0.20 g. of p-toluenesulfonic acid, and 150 ml oftoluene is stirred under reflux using a Dean-Stark moisture trap.Evaporation of the mixture affords a solid which is recrystallized fromethanol to yield N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline, mp102°-106°.

Anilines prepared by the method of Example 175 are set forth in TableIV.

                  TABLE IV                                                        ______________________________________                                                                        Melting                                       Ex.  Compound                   Point                                         ______________________________________                                        176  N--benzylidene-2,4,6-trimethylaniline                                                                    yellow                                                                        oil                                           177  N--benzylidene-2,4-dichloroaniline                                                                       60-63°                                 178  N--(4-methylbenzylidene)-3-chloro-4-                                                                     86-89°                                      methylaniline                                                            179  N--(2,4-dimethylbenzylidene)-2,4-dimethyl-                                                               118-121°                                    aniline                                                                  180  N--(2,4-dichlorobenzylidene)-2,4-dimethylaniline                                                         105-107°                               181  N--(3-nitrobenzylidene)-3,5-dimethoxyaniline                                                             113-116°                               182  N--benzylidene-4-chloroaniline                                                                           60-62°                                 183  N--benzylidene-2,4-dimethylaniline                                                                       oil                                           184  N--(2,4-dichlorobenzylidene)-2,4-dichloroaniline                                                         134-139°                               185  N--(2-chlorobenzylidene)-2-chloroaniline                                                                 111-117°                               186  N--(4-methylbenzylidene)-4-methylaniline                                                                 90-93°                                 187  N--benzylidene-3,5-di(trifluoromethyl)aniline                                                            yellow                                                                        oil                                           188  N--(4-benzyloxybenzylidene)-4-carboethoxy                                                                140-142°                                    aniline                                                                  189  N--benzylidene-3-nitroaniline                                                                            69-72°                                 ______________________________________                                    

EXAMPLE 190 N-(2,4-Dimethylbenzyl)-2,4-dichloroaniline

A mixture of 13.9 g. of N-(2,4-dimethylbenzylidene)-2,4-dichloroaniline,1.89 g. of sodium borohydride and 150 ml of ethanol is stirred underreflux for one hour, allowed to cool and poured into water.Recrystallization from ethanol yieldsN-(2,4-dimethylbenzyl)-2,4-dichloroaniline, m.p. 88°-90°.

Anilines prepared by the method of Example 190 are set forth in Table V.

                  TABLE V                                                         ______________________________________                                                                       Melting                                        Ex.  Compound                  Point                                          ______________________________________                                        191  N--benzyl-2,4,6-trimethylaniline                                                                        oil                                            192  N--benzyl-2,4-dichloroaniline                                                                           oil                                            193  N--(4-methylbenzyl)-3-chloro-4-methylaniline                                                            oil                                            194  N--(2,4-dimethylbenzyl)-2,4-dimethylaniline                                                             72-7°                                   195  N--(2,4-dichlorobenzyl)-2,4-dimethylaniline                                                             70-72°                                  196  N--(3-nitrobenzyl)-3,5-dimethoxyaniline                                                                 amber oil                                      197  N--benzyl-4-chloroaniline 48-49°                                  198  N--benzyl-2,4-dimethylaniline                                                                           28-33°                                  199  N--(2,4-dichlorobenzyl)-2,4-dichloroaniline                                                             84-86°                                  200  N--(2-chlorobenzyl)-2-chloroaniline                                                                     41-44°                                  201  N--(4-methylbenzyl)-4-methylaniline                                                                     50-54°                                  202  N--benzyl-3,5-di(trifluoromethyl)aniline                                                                oil                                            203  N--(4-benzyloxybenzyl)-4-carboethoxyaniline                                                             147-150°                                204  N--benzyl-3-nitroaniline  106-108°                                ______________________________________                                         Example 175 and Examples 176-202, inclusive, in Tables IV and V have been     actually carried out.                                                    

We claim:
 1. A compound of the formula: ##STR5## wherein X represents atleast one substituent selected from the group consisting of (C₁-C₄)alkyl, (C₁ -C₄)alkenyl, (C₁ -C₄)alkynyl, phenoxy, mercapto, amino,(C₁ -C₄)alkylamino, di(C₁ -C₄)alkylamino, halo, trihalomethyl, (C₁-C₄)alkanoyl, benzoyl, (C₁ -C₄)alkanamido, nitro, cyano, carboxy, (C₁-C₄)-carboalkoxy, carbamoyl, sulfamyl, methylenedioxy, phenyl,ortho-phenylene, tolyl, benzyl, halobenzyl and the group ##STR6## R₁ andR₂ are the same or different and are independently selected from thegroup consisting of (C₄ -C₁₂)alkyl, (C₄ -C₁₂)alkenyl, (C₄ -C₁₂)alkynyl,(C₄ -C₁₂)cycloalkylalkyl, (C₇ -C₁₄)aralkyl, and (C₇ -C₁₄)aralkyl inwhich an aromatic ring bears at least one substituent selected from thegroup consisting of (C₁ -C₁₀)alkyl, (C₁ -C₁₀)alkoxy, phenoxy, benzyloxy,methylenedioxy, (C₁ -C₄)alklthio, phenyl, halo, trihalomethyl,adamantyl, (C₁ -C₄)carboalkoxy and nitro; R₃ is selected from the groupconsisting of (C₁ -C₄)alkenyl, (C₁ C₄)alkynyl, benzyl, benzyl bearing atleast one substituent Z, naphthyl, phenyl and phenyl bearing at leastone substituent Z, Z being selected independently of X from the groupconsisting of those from which X is selected with the proviso that X maynot be alkyl only.
 2. A compound as recited in claim 1 wherein Xrepresents at least one substituent selected from the group consistingof (C₁ -C₄)alkyl, halo, carboxy, (C₁ -C₄)carboalkoxy and benzyl.
 3. Acompound as recited in claim 2 wherein R₁ is (C₇ -C₁₄)aralkyl and R₂ is(C₄ -C₁₂)alkyl.
 4. A compound as recited in claim 3 wherein R₁ is benzyland R₂ is n-butyl.
 5. The compound as recited in claim 1;1,1-di-benzyl-3-(3-chloro-4-methylphenyl)-3-phenylurea.
 6. The compoundas recited in claim 1;1,1-di-(n-butyl)-3-(3-chloro-4-methylphenyl)-3-phenylurea.
 7. Thecompound as recited in claim 1;1,1-di-benzyl-3,3-di-(3-chloro-4-methylphenyl(urea.
 8. The compound asrecited in claim 1;1,1-di-(n-butyl)-3,3-di-(3-chloro-4-methylphenyl)urea.
 9. The compoundas recited in claim 1;1-benzyl-1-(n-butyl)-3-(3-chloro-4-methylphenyl)-3-phenylurea.
 10. Thecompound as recited in claim 1;1-benzyl-1-(n-butyl)-3,3-di-(3-chloro-4-methylphenyl)urea.
 11. Thecompound as recited in claim 1;1-benzyl-1-(n-butyl)-3-(4-chlorophenyl)-3-phenylurea.
 12. The compoundas recited in claim 1;1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)-3-phenylurea.
 13. A method ofreducing the cholesterol ester content of an arterial wall, inhibitingatherosclerotic lesion development and treating hyperlipidemia in amammal in need of such treatment which comprises administering to saidmammal an effective amount of a compound as recited in claim
 1. 14. Amethod of reducing the cholesterol ester content of an arterial wall ina mammal in need of such treatment which comprises administering to saidmammal a cholesterol ester-reducing amount of a compound as recited inclaim
 1. 15. A method of inhibiting atherosclerotic lesion developmentin a mammal in need of such treatment which comprises administering tosaid mammal an atherosclerotic lesion development-inhibiting amount of acompound as recited in claim
 1. 16. A method of treating hyperlipidemiain a mammal in need of such treatment which comprises administering tosaid mammal an effective lipid-altering amount of a compound as recitedin claim
 1. 17. A pharmaceutical composition suitable for reducing thecholesterol ester content of an arterial wall, inhibitingatherosclerotic lesion development and treating hyperlipidemia in amammal which comprises an effective amount of a compound as recited inclaim 1 and a non-toxic, pharmaceutically acceptable carrier.
 18. Apharmaceutical composition suitable for reducing the cholesterol estercontent of an arterial wall in a mammal which comprises a cholesterolester-reducing amount of a compound as recited in claim 1 and anon-toxic pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition suitable for inhibiting atherosclerotic lesion developmentin a mammal which comprises an atherosclerotic lesiondevelopment-inhibiting amount of a compound as recited in claim 1 and anon-toxic, pharmaceutically acceptable carrier.
 20. A pharmaceuticallycomposition suitable for treating hyperlipidemia in a mammal whichcomprises an effective lipid-lowering amount of a compound as recited inclaim 1 and a non-toxic, pharmaceutically acceptable carrier.